CN103980198A - Alkaloid Casuarinine H and use thereof in preparation of medicines for treating neurodegenerative diseases - Google Patents
Alkaloid Casuarinine H and use thereof in preparation of medicines for treating neurodegenerative diseases Download PDFInfo
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- CN103980198A CN103980198A CN201310051286.1A CN201310051286A CN103980198A CN 103980198 A CN103980198 A CN 103980198A CN 201310051286 A CN201310051286 A CN 201310051286A CN 103980198 A CN103980198 A CN 103980198A
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- casuarinine
- alkaloid
- extraction
- rattan
- extract
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- 0 C=I=CC=I[C@](C[C@@](*C(N1)=C2C=CC1=O)*1*=N)C[C@]21N Chemical compound C=I=CC=I[C@](C[C@@](*C(N1)=C2C=CC1=O)*1*=N)C[C@]21N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
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Abstract
The invention belongs to the field of medicine technology, relates to lycopodiastrum casuarinoides extract alkaloid Casuarinine H and medicinal new use thereof, and in particular relates to use of the lycopodiastrum casuarinoides extract alkaloid Casuarinine H in preparation of medicines for treating neurodegenerative diseases. Activity study on the lycopodiastrum casuarinoides extract alkaloid Casuarinine H is performed by an oxidative stress in-vitro screening model, and experiments show that the alkaloid Casuarinine H has a an obvious protective effect on cell injury caused by oxidative stress, the alkaloid Casuarinine H can be used alone or in combination, or in combination with suitable excipients, oral or non oral dosage preparation forms such as tablets, capsules, granules or injections are produced according to conventional methods, and the alkaloid Casuarinine H can be used for preparing the medicines for treating the neurodegenerative diseases including but not limited to Alzheimer's disease or Parkinson's disease and the like.
Description
Technical field
The present invention relates to medical technical field, relate to alkaloid Casuarinine H and new medical use thereof in rattan lycopod extract, be specifically related to the purposes of alkaloid Casuarinine H in preparation treatment nerve degenerative diseases medicine in rattan lycopod extract, relate in particular to the purposes of alkaloid Casuarinine H in the nerve degenerative diseases medicines such as preparation treatment alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis in rattan lycopod extract, the present invention relates to Casuarinine H methods of extraction and preparation from rattan lycopod simultaneously.
Background technology
Studies show that, nerve degenerative diseases is as alzheimer's disease (Alzheimer's disease, AD), Parkinson's disease (Parkinson'sdisease, PD), amyotrophic lateral sclerosis (Amyotrophic lateralsclerosis, ALS), Huntington Chorea (Huntington'sdisease, HD) etc. not only have a strong impact on patient's quality of life, and bring very large economical load to society.Although pathogenesis that at present can't those different in kind diseases of clear interpretation, but, a large amount of research datas show, in those nerve degenerative diseases, the neurocyte in specific brain regions district is subject to active oxygen radical (Reactive Oxygen Species, ROS) and attacks, and makes cell generation apoptosis, and then deterioration is until finally there is nerve degenerative diseases in neural network dysfunction.Research also shows, ROS-oxidative stress (Oxidative Stress, OS) plays an important role in developing nerve degenerative diseases is apoptotic.Therefore, the oxygenizement of elimination or minimizing free radical can effectively alleviate or delay nervus retrogression patient's symptom.
Prior art discloses relevant herbal medicine and has shown multicomponent, many target spots, hypotoxic unique advantage aspect treatment nerve degenerative diseases.As, there are the classical prescription of some herbal medicine, proved recipe to obtain compared with successful Application clinically.
Rattan lycopod (Lycopodiastrum casuarinoides(Spring) Holub.) be Lycopodiaceae rattan Lycopodium plant, mainly be distributed in the ground such as south China, southwest and Hubei, Hunan, Fujian, Taiwan, among the people, with all herbal medicine, be mainly used in treating rheumatic arthritis, wound, arthralgia and myalgia etc.Nineteen nineties, the scientific research personnel of China is studied the chemical composition of this plant first, therefrom find to have and similar three the piliganine compounds of selagine (Huperzine A) skeleton structure: huperzinine (Huperzinine), Huperzine C and Huperzine D, and also the acetylcholinesteraseinhibition inhibition of Huperzine C is suitable with selagine.
So far, there is not yet the report of the purposes of alkaloid Casuarinine H in preparation treatment nerve degenerative diseases medicine in relevant rattan lycopod extract.
Summary of the invention
The object of this invention is to provide alkaloid Casuarinine H and new medical use thereof in rattan lycopod extract, be specifically related to alkaloid Casuarinine H and the purposes in preparation treatment nerve degenerative diseases medicine thereof in rattan lycopod extract, relate in particular to the purposes of alkaloid Casuarinine H in the nerve degenerative diseases medicines such as preparation treatment alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis in rattan lycopod extract.
The present invention is by oxidative stress in-vitro screening model; the number of chemical composition deriving from herbal medicine has been carried out to activity research; experiment shows; alkaloid Casuarinine H in rattan lycopod has obvious biological significance: the cell injury that this alkaloid causes oxidative stress has significant protective effect; under 10 μ M concentration, Casuarinine H is to H
2o
2human neuroblastoma cell (SHSY-5Y) damage of induction can produce significant protective effect; Further; described alkaloid Casuarinine H can apply separately or share, or is combined with suitable vehicle, according to ordinary method, makes oral or parenteral formulation; as make tablet, capsule, particle or injection, be applied to the medicine of preparation treatment nerve degenerative diseases.
The invention provides the preparation method of alkaloid Casuarinine H in rattan lycopod extract,
Described activeconstituents Casuarinine H is obtained via the method preparation of the related routine in this area by rattan lycopod over-ground part or its herb, it comprises step: first take rattan lycopod over-ground part or rattan lycopod herb is raw material, adopts solvent-extraction process to make concentrated extract; In the solvent-extraction process adopting, can select the solvent mixture of the single solvents such as water, methyl alcohol, ethanol, acetone or multi-solvents, take 50 ~ 95% ethanol as optimum extraction solvent, refluxing extraction under at room temperature dipping extraction or heating condition, extraction time is 2～3 times, after extracting solution is concentrated, be suspended in appropriate 3% aqueous tartaric acid solution, with isopyknic ethyl acetate extraction 2～3 times; Aqueous tartaric acid solution is with Na
2cO
3regulate pH value to 10, then with chloroform, extract, obtain total alkaloids (chloroform extract), through column chromatography, from rattan lycopod chloroform extract, be prepared into monomeric compound Casuarinine H, called after Casuarinine H, bioactivity research shows that this compound is the direct active substance of rattan lycopod extract opposing oxidative stress, by
1h-NMR, 13C-NMR, 2D-NMR and MS, the chemical structure of having determined this compound is suc as formula I:
Compound: Casuarinine H, [α]
22.5d-17.1 ° of (c0.65, CHCl
3).
1H-NMR（400MHz，CDCl
3）：δ6.44(1H,d,J=9.2Hz,H-2),7.76(1H,d,J=9.2Hz,H-3),3.06(1H,dd,J=18.8,7.1Hz,H-6α),2.51(1H,br?d,J=18.8Hz,H-6β),2.30(1H,m,H-7),1.29(1H,ddd,J=12.8,12.7,3.7Hz,H-8α),1.75(1H,br?d,J=12.8Hz,H-8β),5.23(1H,dd,J=16.8,1.8Hz,H-10a),5.14(1H,dd,J=10.4,2.0Hz,H-10b),5.62(1H,ddd,J=16.8,?10.4,9.6Hz,H-11),2.14(1H,dd,J=9.6,2.9Hz,H-12),1.09(1H,dd,J=12.0,12.0Hz,H-14a),1.64(1H,dd,J=12.0,3.9Hz,H-14b),1.40(1H,m),0.85(3H,d,J=6.4,Me-16),13.30(1H,br?s,NH)。
13C-NMR(100MHz,CDCl3):δ164.9(C-1),118.9(C-2),140.3(C-3),120.5(C-4),143.7(C-5),29.9(C-6),34.2(C-7),42.5(C-8),117.2(C-10),137.3(C-11),49.9(C-12),54.8(C-13),52.2(C-14),26.3(C-15),21.7(C-16);(+)ESI-MS?m/z245[M+H]
+,267[M+Na]
+,511[2M+Na]
+;(+)HR-ESI-MS?m/z245.1649[M+H]
+(calcd?for?C
15H
21N
2O,245.1648).
The present invention further carries out external oxidative stress screening model and studies show that, the cell injury that this alkaloid causes oxidative stress has significant protective effect.Therefore, Casuarinine H can apply separately or share with other drug, or is combined with suitable vehicle, according to ordinary method, makes the treatment that oral or parenteral formulation is applied to nerve degenerative diseases.
Advantage of the present invention is: Casuarinine H is the new compound of finding first, has chemical structure novelty; Casuarinine H is to nerve degenerative diseases, and the alzheimer's disease and the Parkinson's disease that especially have a strong impact on life of elderly person quality have application prospect; Rattan lycopod is widely distributed in China, and ABUNDANT NATUREAL RESOURSES is cheap and easy to get; Rattan lycopod belongs to herbaceous plant, and regenerative power is strong, even if carry out large-scale production, also can not cause resource exhaustion.
Accompanying drawing explanation
Fig. 1 is the neuroprotective activity data result of alkaloid Casuarinine H,
Wherein, Y value is cell survival rate, by mean value (Mean) ± standard deviation (SD), represents, Normal group survival rate is made as 100%, the percentage value of all the other each groups for comparing with normal group,
##p<0.01 is than Normal group; * p<0.05, * * p<0.01 is than H
2o
2damage group, the positive contrast of ACETYLCYSTEINE (n-acetyl-L-cysteine, L-NAC).
Embodiment
With embodiment, the present invention is further elaborated below, but these embodiment have any restriction to the present invention absolutely not.Any change that those skilled in the art do in to the invention process under the enlightenment of this specification sheets all will drop in the scope of claims.
Embodiment 1
Rattan lycopod herb 1kg, pulverizes, with 90% methyl alcohol room temperature cold soaking of 3 times of amounts 24 hours, and totally 3 times.Merge No. 3 times extracting solution, concentrating under reduced pressure, obtains 90g medicinal extract.3% aqueous tartaric acid solution suspendible of 2 times of amounts for medicinal extract, uses with the isopyknic ethyl acetate of suspension and extracts three times, then uses Na
2cO
3aqueous tartaric acid solution is partly adjusted to pH=10, use again chloroform extraction three times, after chloroform extraction part concentrating under reduced pressure, obtain the total medicinal extract 1.1g of alkaloid, then to wait times silica gel (100～200 order) to mix sample, silica gel (200～300 order) with 50 times of amounts carries out column chromatography, uses methylene dichloride: methyl alcohol is as eluent gradient wash-out wash-out (volume ratio 1:0-0:1).Collect methylene dichloride: methyl alcohol (15:1, volume ratio) elution fraction, this component continued silicagel column, adopted methylene dichloride: methyl alcohol 50:1,30:1,10:1 wash-out.To 30:1 elution fraction, adopt preparative HPLC to carry out purifying, with methyl alcohol: water: diethylamine (35:65:0.05%) isocratic elution, collect 39.524min component, obtain 15mg white amorphous powder Casuarinine H.
Embodiment 2
Rattan lycopod herb 1kg pulverizes, with refluxing 3 hours under 80% ethanol room temperature, repeats 3 times, and united extraction liquid, concentrating under reduced pressure obtains medicinal extract 110g.3% aqueous tartaric acid solution suspendible of 2 times of amounts for medicinal extract, uses and the isopyknic ethyl acetate extraction of suspension three times, then uses Na
2cO
3aqueous tartaric acid solution is adjusted to pH=10, with equal-volume chloroform extraction three times.After chloroform extraction part concentrating under reduced pressure, obtain the total medicinal extract 1.3g of alkaloid.Macroporous resin HP-20 on medicinal extract, with water, 50% ethanol, 90% ethanol elution, partly goes up Sephadex LH-20 by 50% ethanol elution respectively, adopts methylene dichloride: methyl alcohol 2:1 wash-out, obtains the Casuarinine H of 13mg by TLC combining data detection.
The neuroprotective test of embodiment 3Casuarinine H
SHSY-5Y cell, after digestion, is suspended from containing in the MEM/F12 nutrient solution of 10% foetal calf serum.With 2 * 10
5the density of individual/milliliter is inoculated in SHSY-5Y cell on 96 well culture plates, and inoculation volume is 100 microlitres/hole, is then placed in containing 5%CO
237 ℃ of constant incubators in cultivate 24 hours.Change the nutrient solution in each hole into fresh MEM/F12 nutrient solution, in administration group, add the testing compound (10 microlitres/hole) of respective concentration, Normal group and H
2o
2damage group adds compound solvent control (10 microlitres/hole).Hatch after 2 hours, at administration group and H
2o
2in damage group, add respectively 1mM H
2o
2(10 microlitres/hole), final concentration is 100 μ M.Continue to cultivate after 24 hours, add 5mg/mL MTT(10 microlitre/hole), carry out viable cell dyeing.Hatch after 3 hours, discard nutrient solution, add 100%DMSO(100 microlitre/hole), and jolting makes it abundant dissolving on rocker machine.Under the wavelength of 490nm, measure the OD value of each group, test-results shows that damage has significant protective effect to Casuarinine H to SHSY-5Y oxidative stress.As shown in Figure 1, wherein, Hu JF-8 represents embodiment 1 gained rattan lycopod activity extract Casuarinine H to the activity data of Casuarinine H.
Claims (7)
1. the alkaloid Casuarinine H compound of formula I,
2. the alkaloid Casuarinine H of claim 1 treats the purposes in nerve degenerative diseases medicine in preparation.
3. by purposes claimed in claim 2, wherein said nerve degenerative diseases is alzheimer's disease or Parkinson's disease or amyotrophic lateral sclerosis.
4. the preparation method of the alkaloid Casuarinine H of claim 1, it is characterized in that, it comprises step: described activeconstituents Casuarinine H is obtained via the method preparation of the related routine in this area by rattan lycopod over-ground part or its herb, it comprises step: first take rattan lycopod over-ground part or rattan lycopod herb is raw material, adopts solvent-extraction process to make concentrated extract; The solvent adopting is selected from the solvent mixture of water, methyl alcohol, ethanol or acetone single solvent or multi-solvents, refluxing extraction under dipping extraction or heating condition under room temperature, extraction time is 2～3 times, after extracting solution is concentrated, be suspended in appropriate 3% aqueous tartaric acid solution, with isopyknic ethyl acetate extraction 2～3 times; Aqueous tartaric acid solution is with Na
2cO
3regulate pH value to 10, then use chloroform extraction, obtain chloroform extract, through column chromatography, from chloroform extract, make monomeric compound Casuarinine H, called after Casuarinine H, by
1h-NMR,
13c-NMR, 2D-NMR and MS, the chemical structure of determining this compound is suc as formula I:
5. by the method for claim 4, it is characterized in that, the extraction solvent adopting is 50 ~ 95% ethanol.
6. by the purposes of claim 1, it is characterized in that, described Casuarinine H applies separately or share with other drug.
7. by the purposes of claim 1, it is characterized in that, described Casuarinine H is combined with vehicle and is made tablet, capsule, particle or injection.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107365316A (en) * | 2017-08-01 | 2017-11-21 | 中国科学院昆明植物研究所 | Lycopodium alkaloid lycoplanineA and its pharmaceutical composition and its preparation method and application |
| CN114392260A (en) * | 2022-02-15 | 2022-04-26 | 重庆市九龙坡区精神卫生中心(重庆市九龙坡区石坪桥医院) | Medicine for relieving anxiety and depression |
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| CN101732312A (en) * | 2009-11-27 | 2010-06-16 | 武汉益维康医药技术开发有限公司 | Huperzine A oral formulation and a preparation method thereof |
| CN102151268A (en) * | 2011-03-28 | 2011-08-17 | 王义明 | Compound preparation for treating Alzheimer's disease and preparation method thereof |
| CN102178680A (en) * | 2011-04-24 | 2011-09-14 | 浙江现代中药与天然药物研究院有限公司 | Long-acting and high-content Huperzine paster and preparation method thereof |
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2013
- 2013-02-08 CN CN201310051286.1A patent/CN103980198B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101732312A (en) * | 2009-11-27 | 2010-06-16 | 武汉益维康医药技术开发有限公司 | Huperzine A oral formulation and a preparation method thereof |
| CN102151268A (en) * | 2011-03-28 | 2011-08-17 | 王义明 | Compound preparation for treating Alzheimer's disease and preparation method thereof |
| CN102178680A (en) * | 2011-04-24 | 2011-09-14 | 浙江现代中药与天然药物研究院有限公司 | Long-acting and high-content Huperzine paster and preparation method thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107365316A (en) * | 2017-08-01 | 2017-11-21 | 中国科学院昆明植物研究所 | Lycopodium alkaloid lycoplanineA and its pharmaceutical composition and its preparation method and application |
| CN107365316B (en) * | 2017-08-01 | 2019-07-26 | 中国科学院昆明植物研究所 | Lycopodium alkaloid lycoplanineA and its pharmaceutical composition and preparation method and application |
| CN114392260A (en) * | 2022-02-15 | 2022-04-26 | 重庆市九龙坡区精神卫生中心(重庆市九龙坡区石坪桥医院) | Medicine for relieving anxiety and depression |
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| CN103980198B (en) | 2016-09-07 |
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